Activation of the PI3K pathway (loss of PTEN) has garnered great interest in prostate cancer as 42% of primary tumors and nearly 100% of metastatic castration-resistant prostate cancers have molecular alterations in this pathway. Thus therapeutic targeting of the PI3K pathway in prostate cancer appears very attractive. Recently, a number of novel inhibitors targeting various components of the PI3K pathway (P13K, AKT, mTORCI, and mTORCI/2) have emerged in early, but promising, clinical development Using preclinical models, we have found that inhibition of the PI3K pathway alone is insufficient to promote tumor regression or apoptosis in PTEN loss prostate cancer. We have generated preliminary data showing that inhibition of the PI3K pathway results in feedback activation of a number of receptor tyrosine kinases (RTK), such as IGF1R and HER2/HER3, that promote prostate cancer cell survival. Furthermore, we find that inhibition of the PI3K pathway induces AR activity in a RTK-dependent manner and concomitant inhibition of AR results in a synergistic profound tumor response in preclinical models. We hypothesize that both AR and PI3K activation suppress prostate cancer cell apoptosis and that inhibition of either pathway alone results in compensatory activation of the other pathway. In this project, we will test this hypothesis and undertake the aggressive preclinical development of combinatorial AR and PI3K pathway inhibition. Specific Aims: 1. To determine the effects of PI3K pathway inhibition in prostate cancer 2. To determine the effects of AR Inhibition on signaling and prostate cancer biology 3. To determine the biologic consequences and antitumor activity of combined PI3K and AR pathway inhibition in prostate cancer